Review Article ThromboticMicroangiopathies · 2017. 12. 4. · to refer to microangiopathic hemolytic anemia associated with vasculitis, infection, pregnancy, medication, or which

International Scholarly Research NetworkISRN HematologyVolume 2012, Article ID 310596, 8 pagesdoi:10.5402/2012/310596

Review Article

Thrombotic Microangiopathies

Mohamed Radhi and Shannon L. Carpenter

Pediatric Hematology/Oncology/Stem Cell Transplant, Children’s Mercy Hospital, Kansas City, MO 64108, USA

Correspondence should be addressed to Mohamed Radhi, [email protected]

Received 9 April 2012; Accepted 10 June 2012

Academic Editors: G. Lucarelli and B. Wachowicz

Copyright © 2012 M. Radhi and S. L. Carpenter. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Thrombotic microangiopathy results from thrombotic occlusion of the microvasculature leading to fragmentation of red bloodcells, profound thrombocytopenia, and a microangiopathic hemolytic anemia with elevation of lactate dehydrogenase and negativedirect Coomb’s test. This constellation of clinical and laboratory findings is not due to one disease entity; rather, it represents avariety of underlying diagnoses. Among the major disease entities are TTP/HUS, which can be congenital or acquired, bacterialinfections, medications, vascular or endothelial pathology like Kasabach-Merritt phenomenon, and stem cell transplantation. Inthis paper, we offer a review of some of the major causes of thrombotic microangiopathy.

1. Introduction

Thrombotic microangiopathy (TMA) results from red cellfragmentation and platelet trapping with subsequent mi-croangiopathic hemolytic anemia and thrombocytopeniaand represents a final common pathway of a multitude ofclinical syndromes. In this paper, we attempt to summarizethe salient features of many of these clinical entities andprovide suggestions to help guide the efforts to differentiatebetween them. This is by no means meant to be an exhaustivediscussion of these disorders, but rather strives to be a usefulsummary of some of the important causes of TMA.

2. Kasabach-Merritt Phenomenon

Kasabach-Merritt phenomenon (KMP) typically describesthrombocytopenia and consumptive coagulopathy in thepresence of a vascular tumor. KMP is very rare, occurringin only 0.3% of congenital hemangiomata. It was initiallydescribed as being associated with a rapidly enlarging infan-tile hemangioma [1]. However, further research has shownthat KMP is most commonly associated with the rare benignvascular tumors Kaposiform Hemangioendothelioma (KHE)and Tufted Angioma (TA) [2, 3]. More than 50% of the casesof KHE and TA occur in the first year of life.

KHE and TA tend to occur on the extremities, neck ortrunk, but can sometimes involve the retroperitoneum. For

this reason, thrombocytopenia in a newborn unexplainedby other routine testing (such as for sepsis) should promptimaging for occult vascular lesions. The pathogenesis of thiscondition has not been fully elucidated, but to the best of ourunderstanding, the abnormal endothelium of these tumorsresults in platelet trapping, fibrin deposition with subsequentred blood cell damage, and a consumptive coagulopathy.Thrombocytopenia is usually severe and hypofibrinogene-mia is present. While microangiopathic features are oftenapparent, anemia is not a common presenting sign unlesssignificant bleeding has occurred. Bleeding into the lesionleads to rapid enlargement of the tumor, continuing thecycle of platelet trapping and activation with consumptionof clotting factors [1]. KMP has been reported as having 30–40% mortality, usually due to uncontrolled bleeding, but alsosecondary to cardiac failure or invasion of vital structures bythe lesion [4].

Historically, interferon alpha has been used successfullyas treatment for KMP, but the side effect of irreversiblespastic diplegia, particularly in children under 1 year of age,has led to this drug falling out of favor, though it is stillused in some cases. First-line treatment now typically reliesupon corticosteroids and vincristine, though no prospectiverandomized trials have been completed comparing thisregimen to an alternate treatment [5, 6]. Use of otherchemotherapies such as cyclophosphamide, actinomycin-D, and methotrexate and of antiplatelet treatments such

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as ticlodipine has been reported [7, 8]. There are studiescurrently underway investigating the benefit of novel ther-apies such as rapamycin. Surgical resection, radiation, andembolization of the lesions have also been reported [4, 9, 10].

3. Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) has clas-sically been defined as the pentad of microangiopathichemolytic anemia, thrombocytopenia, fever, and neurolog-ical and renal compromise. However, the diagnosis requiresonly microangiopathic anemia and thrombocytopenia, withor without ischemic organ damage, and not attributable toan alternate recognizable cause. This has of course increasedboth the prevalence and diversity of the disease. The esti-mated incidence of TTP is 2–10 per million/year [11].

Untreated, the mortality of TTP was historically as highas 80–90%. With the use of plasma exchange treatment,the overall mortality has been reduced to 20–30% [12].The term TTP (or secondary TTP) has also been usedto refer to microangiopathic hemolytic anemia associatedwith vasculitis, infection, pregnancy, medication, or whichdevelops post-stem-cell transplant [13]. We will discuss thoseentities separately. For the purposes of this section of thispaper, we will focus on congenital and idiopathic acquiredTTP.

Recent research has illuminated some of the underlyingpathophysiology associated with this disorder, though manyquestions still remain. TTP is the result of thrombi inthe microcirculation, leading to thrombocytopenia andmicroangiopathic hemolytic anemia due to red cell damagewithin the microthrombi [14]. One of the most excitingdevelopments in the field of TTP has been the identificationof the von Willebrand factor-cleaving protease, ADAMTS13(A Disintegrin and Metalloprotease with ThromboSpondintype 1 repeats). This enzyme is responsible for the cleavage ofextra large multimers of von Willebrand factor (VWF) intosmaller moieties. The lack of this enzyme, either constitu-tionally or acquired, has been linked to the development ofTTP [15, 16]. This phenomenon does not account for all ofthe cases of TTP, however, and further research is requiredto explain the complete link between this enzyme and theclinical variability of the disease [17].

Idiopathic TTP typically occurs due to the developmentof autoantibodies to ADAMTS13, usually type G im-munoglobulins [18]. Measurement of ADAMTS13 activityand inhibitor titers has improved the diagnosis of TTP.Approximately 20–50% of patients with idiopathic TTP willexperience a relapse [12]. Patients’ risk of relapse is some-what predicted by very low ADAMTS13 levels at diagnosis.However, variations in ADAMTS13 activity and inhibitorlevels after treatment has been completed have not beenconsistently predictive of pending relapse, putting the utilityof following these levels into question [12, 19, 20].

Plasma infusion or exchange is the mainstay of treatmentfor acquired TTP [12, 21]. Additional treatment modalitiessuch as steroids, vincristine, cyclophosphamide, antiplateletagents, and Rituximab (anti-CD20 antibody) have also beenused to varying success [22].

Inherited TTP, also known as Upshaw-Schulman Syn-drome, results from genetic mutations in the ADAMTS13gene and represents approximately 10% of those patientswith TTP. This is an extremely rare disorder, estimated tohave an incidence of only 1 : 1,000,000 [17]. It is inheritedin an autosomal recessive pattern, sometimes homozygously,but more often due to compound heterozygosity, and pene-trance can be variable within the same family. Most patientspresent in infancy, but there are patients who have presentedduring the second or third decades of life, and there areindividuals who are known to carry mutations who showno symptoms. This has led to the hypothesis that, in someindividuals carrying 2 mutations, an additional triggeringevent in conjunction with low ADAMTS13 levels is requiredto develop TTP [11, 14].

Transfusions of normal plasma are the standard of treat-ment for congenital TTP. Recombinant and plasma-derivedADAMTS13 replacement products are in development [23].In addition, a novel aptamer which blocks platelet activationin TTP is currently under investigation and has completedphase I studies [24, 25]. Gene therapy has also been suggestedas a treatment for this disorder, though research is still in thepreclinical stages [26].

4. Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS) is characterized bymicroangiopathic hemolytic anemia and thrombocytopeniawith accompanying renal impairment [27]. It can be dividedinto 3 subtypes: diarrhea-associated HUS (D+HUS), pneu-mococcal (also known as atypical or diarrhea negative) HUS,and congenital HUS (which has also been referred to asatypical). While the three entities share clinical features, theunderlying epidemiology, pathogenesis, and treatment aremarkedly different. Like TTP, the term HUS has been usedto refer to a spectrum of thrombotic microangiopathy causedby medications or associated with pregnancy or other clinicalconditions [13, 28]. We will only address the three entitieslisted above in this section of the paper.

Diarrhea-associated HUS (D+HUS) is the most commonsubtype of HUS. It usually occurs in children and is mostcommonly caused by infection with Shiga-toxin producingEscherichia coli O157 (STEC) [29]. The mean incidence ofHUS in children under 18 years of age ranges from 0.28 to0.71 cases per 100,000 persons. The disease is more commonin those <5 years of age, in whom the mean incidencehas been reported between 0.85 and 1.87 cases per 100,000children [29, 30]. D+HUS is also the most common cause ofacute renal failure in children in the USA. Mortality rangesfrom 1 to 33% with the highest mortality in those >60 yearsof age [29].

The pathogenesis of D+HUS results from the productionof Shiga-toxins (Stx) by the infective E. coli. While the mostcommon type of E. coli associated with this illness is theO157 : H7 strain, it is well known that other strains of E.coli may also produce Stx. STEC lead to a food- or water-borne diarrheal illness that can be bloody or nonbloody.The disease progresses to HUS due to the release of Stxin the intestine, which then are translocated across the gut

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epithelium into the circulation. The primary target of Stxis a unique digalactose moiety in the glycolipid Gb3. Theprimary locations of Gb3 in the human body are vascularendothelial cells, particularly in the glomeruli. Exposure toStx damages the endothelium, resulting in the release oftissue factor and exposure of the platelets to extra large vonWillebrand factor multimers and collagen. This then triggersactivation of the platelets and the coagulation cascade andleads to thrombus formation. The impact of the actions ofStx in these locations results in microangiopathic hemolyticanemia and thrombocytopenia. In addition, Stx has alsobeen shown to bind to and directly activate platelets viathe Gb3 receptor [31]. HUS does not typically result inhypofibrinogenemia [32, 33].

Treatment for D+HUS relies mainly upon supportivecare [21]. There have been recent studies regarding SYN-SORB Pk, an agent composed of silicone dioxide particleslinked to the Pk trisaccharide that is responsible for Stxbinding to the endothelial cell surface. This is meant to blockthe translocation of Stx into the circulation. Monoclonalantibodies to Stx are also under investigation [32]. In exper-imental studies in mice these antibodies have been shown toneutralize Stx [33]. Studies in healthy volunteers have shownthat they are well tolerated [34].

HUS associated with pneumococcal infection (D-HUS orP-HUS) is one of the atypical forms of HUS. It is much lesscommon that D+HUS accounting for only approximately5–10% of HUS cases overall, though it may be responsiblefor as many as half of D-HUS cases. It has been associatedwith a higher morbidity and mortality than D+HUS, thoughincreased awareness and improved treatment has improvedthis finding. P-HUS tends to occur in very young children,with the average age typically under 1 year. There is aslight male preponderance. Most cases have fairly severepneumococcal pneumonia and evidence of pleural effusion.Meningitis has also been reported. The overall mortality rateis currently approximately 10%, which is much improvedfrom previous reports of mortality from 29–50% [35, 36].

Streptococcus pneumoniae release neuraminidase, anenzyme that results in desialylation of red blood cell mem-brane proteins and exposure of the Thomsen-Friedenreichcryptantigen (T-antigen). The T-antigen is a ubiquitousantigen on human blood cells to which all people have IgMantibodies. Exposure of this antigen leads to hemolysis,thrombocytopenia, and microthrombi. It is not clear if thesesymptoms are antibody mediated or are a result of anothermechanism [35].

Treatment for pneumococcal-associated HUS relies ontreatment of the underlying infection. In addition, support-ive care with dialysis may be required for those patients inkidney failure. Plasma exchange therapy has also been usedin a subset of patients. Many patients require blood producttransfusion, though exposure to plasma should be limitedbecause of the possibility of worsening the hemolysis dueto infusion of IgM anti-T antibody [35]. Vaccination againstpneumococcus would reasonably be expected to reduce theprevalence of P-HUS, since the most common serotypesassociated with HUS are included in the vaccine. However, ithas recently been shown that serotype 19A may have emerged

as an important invasive pathogen leading to P-HUS. Thisserotype is not included in the PCV7 [35].

Another important type of atypical HUS (aHUS) isassociated with complement deregulation. This may presentcongenitally or later in life. It is thought that up to one-third to one-half of patients with aHUS have a mutation inone of the complement regulatory proteins. The deficiencyof factor H, a regulatory glycoprotein in the alternativecomplement pathway, leads to a form of congenital HUS.Factor H provides protection from complement activation.The absence leads to overactivity of the alternative comple-ment pathway and subsequent features of HUS. Mutationscausing deficiencies in factor I, C3, and membrane cofactorprotein CD46 have also been reported [31, 37, 38]. Gain-of-function mutations in complement factor B and C3,have been identified in families with aHUS and persistentactivation of the alternative complement pathway. Familiescarrying mutations show incomplete penetrance of diseaseand may be modulated by the presence or absence of othercomplement gene variants [38–40]. Autoantibodies to factorH which develop in individuals with mutations in factor Hrelated proteins 1 and 3 have also been implicated in thepathogenesis of the disease [41].

The prognosis for aHUS is grim, with mortality ap-proaching 25% in the acute phase and as many as 50% ofpatients developing end stage renal disease. If transplantationis attempted, 60–100% of patients will experience a relapse,which almost inevitably results in loss of the renal graft [37].Outcome is somewhat dependent upon the specific mutationleading to disease [36].

Treatment relies on infusion of plasma which containsthe missing factor. In the case of those patients with autoan-tibodies, plasma exchange and immunosuppressive therapyhave also been successful [41]. Recent studies regarding theuse of the recombinant complement inhibitor eculizumabhave been promising, particularly in those patients who havefailed plasma-replacement therapy [37].

5. Transplant-Associated MAHA

Microangiopathic hemolytic anemia (MAHA), also calledposttransplant thrombotic microangiopathy (TA-TMA) hasbeen described as a complication of bone marrow trans-plantation, both autologous and allogeneic with variableincidence rates ranging from 0 to 74% depending on thediagnostic criteria used to make the diagnosis [42, 43]. Itis also a well-known complication following solid organtransplants, such as kidney transplants, with a variable timefrom transplant to diagnosis and could be due to viral infec-tions, arise de novo, or be related to the use of calcineurininhibitors, mainly the microemulsion form of cyclosporine[37, 44]. TMA was observed in 26 of 188 patients with renaltransplants with an incidence of 14% with the majority ofthese patients having no systemic manifestation of TMA.It has also been reported following liver transplantation[45]; five of 100 patients who received Living Donor LiverTransplant (LDLT) developed TMA with an incidence of 5%and at a median interval of 18 days following transplant.Another major factor in the development of TMA is drugs

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used for Graft Versus Host Disease (GVHD), mainly FK506and cyclosporine [44] or with other GVHD prophylaxis[46]. Factors that can contribute to this condition includehigh-dose chemotherapy for autologous stem cell transplant(ASCT), conditioning regimen for allogeneic stem cell trans-plant, total body irradiation, and use of immune suppressivetherapy [38, 47, 48].

The role of GVHD and renal involvement in thepathogenesis of TA-TMA has also been investigated [41].Changsirikulchai et al. [49] reviewed 314 renal autopsieson patients who died after their first hematopoietic stemcell transplant over a 7-year period. Twenty percent ofautopsies reviewed showed TMA, with an additional 15%with evidence of thrombus formation. The risk of TMA inthat patient population increased 4-fold with incidence ofacute GVHD, independent of the use of cyclosporine. Thepresence of acute GVHD was an independent risk factorin the development of TA-TMA in the multivariate analysisin addition to sex mismatch, higher doses of total bodyirradiation (TBI), and viral infections.

In addition to the significant renal involvement withacute GVHD, TA-TMA has also been found to involvethe gut tissue [50]. In a study of 16 patients with TA-TMA, all were found to have acute GVHD. Seven patientswere retrospectively diagnosed with TA-TMA, while 9 werespecifically investigated for it. All patients that were ret-rospectively diagnosed died as a result of increasing theimmune suppression intensity due to the impression that itwas purely gut GVHD, while 8 of the other nine patientsimproved following reduction of immune suppression. Sixof those patients were alive one year following transplant.

Infections have also been shown to be associated withMAHA after transplant; bacterial infection with Helicobacterpylori was found to be associated with six patients among74 consecutive transplants through involvement of elevatedcytokines [51]. Viral infections such as parvoB-19, CMV, andHHV-6 have also been implicated as a cause of TA-TMA.Typically postinfectious cases are due to reactivation of theseviruses within the first 3–6 months after transplant. Viralinfections should be considered in recipients of transplantwho develop refractory cases of TA-TMA [39, 52, 53].

6. Pregnancy-Associated MAHA

Pregnancy-associated thrombotic microangiopathy is a rarebut serious disorder that is associated with significant mater-nal and perinatal morbidity and mortality, due to the depo-sition of fibrin and platelet thrombi in the microcirculationof the placenta. It has been reported to occur in 1 : 25,000–1 : 100,000 pregnancies [54, 55]. Pregnancy can precipitatethe disease for the first time or can exacerbate the recurrenceof an existent condition [56, 57]. Pregnancy-associatedmicroangiopathy typically occur during late pregnancy [58];however, it has also been reported in the first trimester ofpregnancy [59], in which case the patient was managed veryintensely with continuous plasma therapy throughout thepregnancy. Both mother and fetus survived without compli-cations. In reviewing the Oklahoma TTP-HUS registry in 335patients, Terrell et al. [60] did not find any gender or race

predilection that was associated with pregnancy-associatedmicroangiopathy, as well as with hematopoietic stem celltransplant or drugs.

Martin et al. recently published data on the largest collec-tion of pregnancy-associated microangiopathy [53] encom-passing over 4 decades. One hundred and sixty-six patientswith pregnancy-associated thrombotic thrombocytopenicpurpra were reported on. Only patients who met specificdiagnostic criteria were included in the study. Patients eitherhad their first episode (n = 106) or recurrent episode (n =32). Median time presentation was 23.7 ± 9 weeks and22 ± 10 weeks, respectively. The only significant laboratorydifferences between both groups were hemoglobin andhematocrits (6.8 versus 11.4 g/dl and 19% versus 25%, resp.).Perinatal and maternal mortalities were high in both groups(32% versus 44% and 26% versus 10.7%); however, bothmortality rates were significantly lower in the years after 1980compared to before that year. One of the confusing clinicalpictures was the association of pregnancy-associated TTPand HELLP syndrome (Hemolysis, Elevated Liver enzymes,Low Platelets), which had both preeclampsia/eclampsia andTTP concurrently. This was reported in 29 of the 166 patientsin the series and significantly increased maternal mortalityfrom 21.8% to 44.4%.

Pregnancy-associated microangiopathy can be confusedwith other medical and obstetrical conditions such assevere preeclampsia/eclampsia, HELLP syndrome, sepsis,and pregnancy-induced fatty liver changes [57, 61]. Theconfusion in making the diagnosis usually happens due tothe non-specific clinical and laboratory criteria needed tomake the diagnosis. This is more of a problem when theinitial management is done by physicians who are not accus-tomed to taking care of these patients. Stella et al. reportedon 14 cases of pregnancy-associated microangiopathy in12 pregnancies by reviewing the charts of these patients[62]. 4/12 cases were evaluated in the ER initially and weregiven the diagnoses of domestic violence, gastroenteritis,ITP, and panic attack. 2/4 patients were discharged homemultiple times before hospitalization. 8/12 patients wereseen by obstetric services; however, all were given thewrong diagnosis, mainly HELLP syndrome, despite of beingnormotensive and having no proteinuria. Half of the patientsin the series were diagnosed before 24 week gestation butonly 3 had term live births.

Over the last 2 decades, there has been increasingevidence that ADAMTS13 is significantly involved in thepathogenesis of pregnancy-associated microangiopathy. Thiscould be due to congenital deficiency of the enzyme activitywhich is usually severe or due to the presence of inhibitorswith less sever deficiency [63, 64]. However, some patientswith pregnancy-associated microangiopathy were found tohave a normal enzyme activity while other patients with TTPdue to other clinical syndromes had low enzyme activity[64]. The congenital deficiency of the ADAMTS13 activity isalso known as Upshaw-Schulman Syndrome (USS) [58]. Intheir research paper, Fujimura and colleagues [64] reporteda series of 15 pregnancies with this syndrome. Thirty-sevenpatients were identified with the syndrome in 32 families.Nine females with a total of 15 pregnancies developed

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significant thrombocytopenia during the second half of theirpregnancies leading to stillbirth in 8 out of total 16 babies.Eight of the nine women had heterozygous mutations andonly one had a homozygous abnormality.

Although ADAMTS13 enzyme deficiency (both congen-ital and acquired) is the main underlying mechanism inpregnancy-induced microangiopathy, dysregulation of alter-native C3 convertase enzyme, due to mutations in the genecoding for the protein has also been shown to cause an atypi-cal form of HUS during pregnancy (mainly involvement withrenal involvement and not due to Shiga toxin) [54]. In aretrospective analysis of 100 women with this rare and ill-defined type of HUS, it was found to be associated with preg-nancy in 21 patients (21% incidence). The disease occurredduring the first pregnancy in 38% and occurred mainlyduring postpartum period (79%). The unusual featureof this syndrome was the disproportionate severe renalinvolvement compared to the thrombocytopenia; 81% ofpatients required hemodialysis during the acute phase while61% eventually reached end-stage renal disease in less than amonth from the beginning of the episode. On the other hand40% of patients had a platelet count of >100,000/mm3.

A variety of the therapeutic interventions have been triedwith pregnancy-induced microangiopathy (and other formsof TTP) with limited success. Therapies such as steroids,antiplatelet agents, IVIg, and even splenectomy have beentried [59]. Not until plasma infusion and plasma exchangewere introduced that the survival rate increased from 10% upto 80% currently [59, 64]. Plasma exchange and/or plasmainfusion need to be initiated whenever there is a goodsuspicion of microangiopathy. In general this therapy willhave to be continued to the end of delivery or throughoutthe postpartum period [56, 59, 61, 64].

7. MAHA Secondary to Vasculitis

MAHA has also been reported in systemic vasculitis due toa variety of causes. One of the clinical dilemmas when itcomes to systemic vasculitis is the overlap of manifestationsof both disorders. One of the earliest reports has been byRoss et al. [65] in 1996 when they reported the incidence of2 cases of MAHA that was associated with a case of Wag-ner’s granulomatosis with positive antineutrophil antibodies(ANCAs) and another case of Guillain-Barre syndromewith positive nerve biopsy for ANCA with specificity tomyeloperoxidase. A more common association of systemicautoimmune disorders and MAHA is usually with systemiclupus erythematosus (SLE), with large number of casereports and small case series [62, 66–68].

In a single-institution large series of patients with SLEand MAHA, Kwok et al. [69] retrospectively reviewed thedata on 1203 patients with SLE over a 6-year period. Twenty-six patients were found to have MAHA in addition to theirSLE diagnosis-87 patients without MAHA matched for ageand sex were also included as controls. The study showedthat SLE is an independent risk factor for the developmentof microangiopathy and that this risk was associated withhigher SLE disease activity index (SLEDAI). The study alsoshowed that infection was the only independent risk factor

for mortality for those TTP patients. MAHA has been alsoreported in a large variety of connective tissue disorders otherthan SLE, including systemic sclerosis, rheumatoid arthritis,dermatomyositis, and Still’s disease [70, 71].

Similar to other conditions with microangiopathy andMAHA, ADAMTS 13 enzyme has been linked to thepathophysiology of MAHA in autoimmune disorders. Severereduction in the enzyme activity as well as the presence ofinhibitors has been consistently found in patients with SLEand other similar disorders. Since ADAMTS 13 deficiencyis considered very rare in SLE and similar disorders withMAHA, testing for this enzyme is considered a good methodto distinguish between the two [65, 67, 70].

8. Summary

MAHA is a rare disorder that has the hallmark of fragmentedred blood cells and thrombocytopenia that is nonimmune innature. MAHA is not a single disease or even a single groupof disorders; rather it is a spectrum of disorders that usuallypresent as an HUS/TTP picture. TTP/HUS is caused by a vastarray of different agents (drugs, toxins, infections, pregnancy,and autoimmunity) that damage the endothelium via mul-tiple and varied mechanisms. Functionally altered endothe-lium provokes intravascular platelet aggregation, resulting inthe variable clinical manifestations of the syndrome. Becauseof the rarity of these disorders and the nonspecific clinicaland laboratory features, this diagnosis (and its underlyingcauses) can be easily overlooked or missed leading to the highmorbidity and mortality that can be seen with this problem.Therefore, when a patient presents with unexplained throm-bocytopenia and a Coombs-test-negative hemolytic anemia,a presumptive diagnosis of MAHA should be considered.One of the newer advancements in the management of thisdisorder is the discovery of association of the ADAMTS13enzyme’s level and activity with TTP that has led to earlierand improved detection rate which was translated to bettersurvival. No specific therapy can be claimed to cure thisgroup of disorders, however, few interventions have beenproven to be helpful (and even life saving) in some disorderssuch as the use of plasma infusion and plasma exchange inthe management of TTP.

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Review Article ThromboticMicroangiopathies · 2017. 12. 4. · to refer to microangiopathic hemolytic anemia associated with vasculitis, infection, pregnancy, medication, or which